We have demonstrated that co-exposure to polychlorinated biphenyls (PCBs) and methylmercury (MeHg)-two of the major neurotoxicants found in fish from the Fox River-synergistically increases the release of dopamine (DA) in striatal tissue and alters intracellular calcium concentrations in cells in culture. The experiments we now propose will allow us to test the hypotheses that: (i) developmental exposure to PCBs and MeHg will induce neurochemical changes similar to those we have seen in the adult; (ii) these changes are due to enhanced release of DA and alterations in intracellular calcium; (iii) these changes will induce oxidative stress that may lead to increased programmed cell death and (iv) this developmental neuronal re-modeling will lead to persistent changes in behavior. In order to test these hypotheses we will first carry out a series of in-vitro experiments using intact brain slices and synaptosomes from developing rat striata to confirm results we obtained in the adult animal. In these in-vitro experiments we will measure media and cellular DA levels; intracellular calcium concentrations, hydroxyl radical formation and lipid peroxidation. These data will aid in the in- vivo in the in-vivo experiments in which the developmental consequences of exposure to these contaminants will be determined. In developmentally exposed animals we will also measure extracellular DA and hydroxyl radical concentrations in frontal cortex and striatum using in-vivo microdialysis, as well as indices of apoptosis (DNA strand breaks, caspase-3, morphological changes) in the substantia nigra of both pre- weaning and adult animals. These experiments will: (1) aid in understanding the mechanisms by which co-exposure to these contaminants alter behavior; (ii) provide developmental data that may justify revision of fish consumption guidelines currently based on exposure to single contaminants and (iii) and most importantly provide information for interventional/educational purposes since these contaminants, localized in different tissues within the fish will allow for changes in the choice of species and the preparation and consumption of fish from the Fox River.